Subtype-Specific Brain Atrophy and White Matter Alterations in Mild Cognitive Impairment

Background/Objectives: Identifying pathological distinctions among mild cognitive impairment (MCI) subtypes is important for differentiating dementia. The purpose of this study is to investigate subtype-specific structural alterations in amnestic MCI (aMCI) and non-amnestic MCI (naMCI) and evaluate their potential as imaging biomarkers for subtype classification. Methods: T1 and DTI MRI data from two independent cohorts were analyzed, including a discovery dataset (58 aMCI, 35 naMCI, and 95 NC) and a replication dataset (61 aMCI, 39 naMCI, and 67 NC). Surface-based morphometry and automated fiber quantification (AFQ) were used to examine cortical thickness and white matter microstructure. Mediation models were used to explore the links between brain structure and cognitive outcomes. A logistic regression model was applied to evaluate classification performance. Results: The aMCI exhibited right hippocampal atrophy. In the naMCI, reduced cortical thickness was observed in the right anterior cingulate cortex (rACC) and opercular inferior frontal gyrus, along with increased fractional anisotropy (FA) in the right inferior fronto-occipital fasciculus (IFOF). These alterations were linked to domain-specific cognitive deficits. Moreover, partial mediation effects of IFOF FA values were observed in the link between rACC thickness and cognitive outcomes. Furthermore, these structural alterations effectively distinguished between aMCI and naMCI, showing stable performance across independent datasets (Accuracy = 0.821, AUC = 0.904). Conclusions: Our findings reveal distinct structural alterations across MCI subtypes, providing deeper insight into the heterogeneous mechanisms of dementia and supporting the potential of imaging markers for the diagnosis of MCI subtypes.